Chapter 31 Drugs for Treatment of Congestive Heart Failure

1. Chapter 31Drugs for Treatment of Congestive Heart Failure

2. Contents • Overview • Cardiac glycoside • Diuretics • ACE inhibitors •  receptor blockers • Others

3. A. Overview 1.Pathophysiological changes of congestive heart failure (CHF) (1) Function and structure changes (2) Increased sympathetic activity and down regulation of  receptor (3) Activated renin-angiotensin-aldosterone system (RAAS)

5. Cardiac failure Cardiac output Blood supply Venous pressure Renal blood flow Renin - angiotension Ⅱ Venous hyperemia Aldosterone Pulmonary circulation: cough, emptysis, dyspnea Systemic circulationhyperemia: jugular vein distension, edema Sodium and water retention Changes of hemodynamics in CHF

7. A. Overview 2. Grades of CHF Ⅰ(A): no symptoms Ⅱ(B): physical activities were limited and symptoms could be induced by general activity Ⅲ(C): physical activities were markedly limited Ⅳ(D): symptoms appear even at rest

8. A. Overview 3. Therapeutic strategies in CHF (1) Increasing contractility of the cardiac muscles (2) Inhibiting RAAS (3) Decrease sympathetic activity (4) Dilating vessels (5) Diuresis  Cardiac remodeling Decrease overload

11. B.Digitalis Digoxin 地高辛

12. B.Digitalis 1. Pharmacological effects (1) Positive inotropic effects inhibiting Na+-K+-ATPase, free Ca2+  excitation-contraction coupling  cardiac output  organ blood supply  Vmax  diastolic duration   venous return   coronary blood supply  cardiac oxygen consumption 

13. Inhibition of Na+-K+-ATPase by digitalis and potentiation of cardiac muscle contraction

16. B.Digitalis (2) Negative chronotropic effects Reflex inhibition of sympathetic activity cardiac output   Sympathetic activity   HR  Increasing vagal activitydirectly

17. B.Digitalis (3) Electrophysiological effects decreasing automaticity of sinoatrial node slow conduction increasing automaticity of Purkinje fibres shortening ERP of fast response cells Mechanisms: intracellular Na+, K+, Ca2+ MDP , afterdepolarization

18. Overdose: Na+, K+, Ca2+   MDP   afterdepolarization Electrophysiological basis for digitalis overdose

19. B.Digitalis (4) Other effects Nervous system autonomic nervous system: NE  central nervous system: CTZ D2 receptor Neuroendocrine system inhibiting RAAS increasing ANP（心房钠尿肽） Kidney increase blood supply of kidney diuretic effect: decrease Na+ resorption

20. B.Digitalis 2. Clinical uses (1) CHF especially associated with atrial fibrillation and sinus tachycardia (2) Arrhythmias atrial fibrillation atrial flutter paroxysmal surpraventricular tachycardia

21. B.Digitalis 3. Adverse effects (1) Gastrointestinal effects nausea, vomiting, etc. (2) CNS effects alteration of color perception（色视, such as yellow vision 黄视）; headache, fatigue, confusion, etc.

22. B.Digitalis (3) Cardiac toxicity arrhythmias：prematural beats,tachycardia， atrioventricular block, sinus bradycardia, etc. Prevention：Dose individualization Avoiding provocation factors: plasma K+ , and drug interactions, etc. Treatment：KCl, phenytoin sodium or lidocaine, i.v. Atropine: A-V block, sinus bradycardia Fab segment of digoxin antibody, i.v.

23. Drug interactions that probably induce digitalis cardiotoxicity

24. B.Digitalis 4. Administration (1) Loading + maintaining doses • full dose (digitalization) + maintaining doses • for severe patients (2) Maintaining dose given daily reaching steady state of plasma concentration with 1 week (digoxin) for stable patients

25. B.Digitalis 5. ADME and properties of different digitalis drugs (1) Moderate-acting:digoxin 地高辛 (2) Long-acting：digitoxin 洋地黄毒苷 digitalization + maintaining doses (3) Short-acting：deslanoside 西地兰, 去乙酰毛花苷 acute attack of CHF

27. Different elimination modes of digoxin and digitoxin

28. C.Diuretics 1. Pharmacological effects • Reduce plasma volume • Reduce Na+-Ca2+ exchange in vessel smooth muscle cells 2. Clinical uses • CHF: grand I – IV (mainly used in II –III), alone or combined with other drugs • Edema, hypertension, etc. 3. Adverse effects plasma level of renin  hypokalemia hyperuricemia hyperglycemia hyperlipidemia

29. Therapeutic effects of diuretics in CHF

30. D.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists ACEI: captopril 卡托普利 enalapril 依那普利 AT1 receptor antagonists: losartan 氯沙坦 irbesartan 伊白沙坦

32. D.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists ACEI 1. Pharmacological effects • Inhibiting the production of Ang II • vasoconstriction ; sodium retention ; • cardiac remodeling (myocardial hypertrophy)  • Inhibiting the degradation of bradykinin • vasodilatation  • Increasing ANP and scavenge free radicals

33. PGI2 NO Actions of ACEI Inactive peptide Angiotensin II brandykinin Angiotensin I ACEI (—) B2 receptor ACEI ACE Circulation and local tissues (—) ACE Circulation and local tissues Vasodilatation Anti-proliferation, anti-hypertrophy

34. Box Actions of angiotensin II • Constricting vessels, increase peripheral resistance and returned blood volume. • Increasing sympathetic tension, promote release of sympathetic transmitter. • Stimulating release of aldosterone. • Inducing expression of c-fos、c-myc、c-jun rapidly.

35. D.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists • Cardiovascular effects • Decrease resistance of peripheral vessels • Dilate coronary artery, increase blood supply of heart and kidney, improve cardiac and renal function • Reverse myocardial hypertrophy and ventricular remodeling

36. D.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists 2. Clinical uses (1) CHF increase motor tolerance decrease mortality (2) Hypertension

37. D.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists 3. Adverse effects Hypotension • Cough and angioedema • Hyperpotassemia • Contraindications: pregnancy and stenosis of renal artery

38. D.Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists AT1 receptor antagonists Compared with ACEI: • Blocking actions of angiotensin II directly • Not influencing bradykinin metabolism • Protecting renal funtion • Used for CHF and hypertension

39. E. receptor blockers Conmmonly used: Carvedilol 卡维地洛, labetalol 拉贝洛尔 1. Pharmacological effects (1) Blocking effects of catecholamines on myocardium: decreasing heart rate and cardiac oxygen demand (2) Up-regulating  receptor (3) Inhibiting RAAS and VP (vosopressin, 加压素): anti- myocardial hypertrophy and remodeling (4) Blocking -receptor and anti- free radical (5) Anti-arrhythmic and anti-hypertensive effects

40. E. receptor blockers 2. Clinical uses (1) CHF: grand II - III decrease of mortality (2) Other uses: hypertension, arrhythmias, angina, etc.

41. E. receptor blockers Therapeutic effects of β receptor antagonists on cardiac function in CHF patients

42. E. receptor blockers 3. Adverse effects • Inhibition of cardiac function • Contraindications: • severe heart failure severe A-V block hypotension bronchial asthma

43. F.Other drugs 1. PDE-III inhibitors milrinone 米力农, vesnarinone 维司力农， amrinone安力农 • Positive inotropic drugs • Hypotension, thrombocytopenia, etc. 2.  receptor agonists dobutamine多巴酚丁胺 • Positive inotropic drugs • Arrhythmias, etc.

44. F.Other drugs 3. Vasodilators cardiac preload and afterload , output  4. Calcium channel blocker 5. Calcium sensitizers

45. Action modes of positive inotropic drugs

46. Limit activity Digitalis ACEI Limit Na+ strategies  blockers Low Na+ combined thiazides Loop diuretics Dilator Positive inotropic drugs Ⅳ Ⅱ Ⅲ grads Therapeutic strategies of CHF